Physiology of incretins in health and disease

Abstract

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

Figure 1. Proposed mechanisms involved in stimulating L-cell secretion

Absorption of nutrients over the luminal (brush border) membrane may be the predominant mechanism in humans, although other signals may include neurotransmitters, hormones and bile acids (see text for details). cAMP: cyclic adenosine monophosphate. GIP: glucose-dependent insulinotropic polypeptide. Glc: glucose. GLP-1: glucagon-like peptide-1. GRP: G-protein-coupled receptor. Na: sodium. NEFA: non-esterified fatty acid. Reproduced with kind permission from [122] (Springer Science+Business Media; Diabetologia, 2011, 54:10-18, Nauck et al., Fig. 1).

Figure 2. Impaired regulation of the incretin effect in patients with type 2 diabetes

Insulin secretion rates (ISR) in healthy control subjects (upper panel) and patients with type 2 diabetes (lower panel) following low (25 g), medium (75 g), and high (125 g) oral glucose loads (closed symbols) and corresponding isoglycemic intravenous glucose infusions (open symbols). Figures in brackets indicate the amount of glucose infused to mimic the glycemic excursion following the oral glucose. ^* p < 0.05. IIGI: isoglycemic intravenous glucose infusion. ISR: insulin secretion rate. OGTT: oral glucose tolerance test. Reproduced with kind permission from [110] (The Endocrine Society, J Clin Endocrinol Metab, 2011, 96:373-345, Bagger et al., Fig. 2c).

Figure 3. GLP-1 response to glucose

A: Integrated "total" GLP-1 response to oral glucose (light grey bars) or mixed meal (dark grey bars) in type 2 diabetic patients, expressed as percentage of the response in matched non-diabetic control subjects. Figures in the bars refer to the number of type 2 diabetic patients (upper row) or control subjects (lower row) studied. Figures below the bars refer to the original studies. B: Meta-analysis of published studies reporting GLP-1 responses in healthy individuals and subjects with type 2 diabetes after a 75g oral glucose tolerance test and/or a standardized mixed meal. GLP-1: glucagon-like peptide-1. CI: confidence interval. Modified and reproduced with kind permission from [122] (Springer Science+Business Media, Diabetologia, 2011, 54:10-18, Nauck et al., Fig. 2b).